Molecular underpinnings of addiction produce strong addiction-related memories

January 11, 2017

Addiction-related memories are exceptionally strong and stable, suggesting that addictive drugs remodel the brain's circuitry in a prominent and lasting way. In the past decade, researchers have used mouse models to unravel how cellular changes in the nucleus accumbens (NAc), a brain structure involved in action selection associated with arousal and reward, may contribute to addiction-related behavior. Whereas neuronal remodeling in the NAc explains a wide range of addictive behaviors, it is not required for all of them, according to a study published today in The EMBO Journal.

A research team led by Oliver Schlüter (University of Pittsburgh, PA, USA) found that cocaine-induced place preference in – returning to places where the drug was previously received – does not depend on lasting rewiring of neurons in the NAc. This finding is an important step towards a better understanding of the cellular and molecular underpinnings of , paving the way for the development of effective therapeutics.

Taking cocaine leads to the generation of immature neuronal contacts called silent synapses in the NAc. Silent synapses, as the name indicates, are not very active. However, after quitting drug abuse, they mature and become stronger, or "unsilenced", as researchers call it. Unsilencing synapses leads to massive NAc rewiring during drug withdrawal and forms the basis of many addictive behaviors. The process may explain why drug craving often increases over time in the first weeks of abstinence.

Previous work on silent synapse-based NAc remodeling has focused on addiction paradigms where animals learn to associate an activity, like pressing a lever or poking their nose into a hole, with receiving drugs. This type of learning is often referred to as "operational conditioning". In their present study, Schlüter and his colleagues tested a form of "Pavlovian learning", where the animal learns passively. Mice were injected with cocaine and placed into one of two compartments of a cage to learn to associate cocaine with the smell, feel and look of that location. After a withdrawal phase, the mice were tested for their memory of the drug-context association. When they were placed back into the two-compartment cage they preferred to reside in the compartment they had learned to associate with feeling high.

The researchers then tested if this learning paradigm would also lead to a rewiring of the NAc and found that it did. Just like in operational conditioning paradigms, silent synapses formed and were unsilenced during withdrawal. But was this rewiring also essential for the mice to remember place preference after withdrawal?

To address this question, the researchers made use of mice with mutations that affect different aspects of synapse unsilencing. They found that mice remember the place where they received cocaine even if synapse unsilencing in the NAc is impaired. Thus, whereas synapse unsilencing and NAc remodeling underlies many addictive behaviors, cocaine-induced place preference is not one of them. This result is an important step towards a better understanding of the molecular and cellular basis of addiction.

Explore further: The yin and yang of overcoming cocaine addiction

More information: Calcium-permeable AMPA Receptors and Silent Synapses in Cocaine-conditioned Place Preference. DOI: 10.15252/embj.201695465

Related Stories

Addiction silences synapses in reward circuits

August 2, 2016

In addiction, cues in the environment can form strong associations with the drug of abuse. A new study in Biological Psychiatry suggests that alterations in silent synapses, inactive connections between neurons, could be ...

Recommended for you

Curb your immune enthusiasm

January 19, 2017

Normally when we think of viruses, from the common cold to HIV, we want to boost people's immunity to fight them. But for scientists who develop therapeutic viruses (to, for example, target cancer cells or correct gene deficiencies) ...

Why the lights don't dim when we blink

January 19, 2017

Every few seconds, our eyelids automatically shutter and our eyeballs roll back in their sockets. So why doesn't blinking plunge us into intermittent darkness and light? New research led by the University of California, Berkeley, ...

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

BubbaNicholson
not rated yet Jan 12, 2017
Flawed paradigm. 250mg of healthy adult male facial skin surface lipid taken p.o. alleviates human drug addiction without withdrawal symptoms.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.